(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (POT)
(19) World Intellectual Property Organization
International Bureau
iiiiiiiiiiiiiiiiiiiiiBini
(43) International Publication Date (10) International Publication Number
4 October 2001 (04.10.2001) PCT WO 01/72220 Al
(51) InternatioDal Patent Classification^: A6IB 5/00, 10/00
(21) International Application Number: PCT/USOl/09673
(22) iDtemational Filing Date: 26 March 2001 (26.03.2001)
(25) Filing Language: EngUsh
(26) Publication Language: English
(30) Priority Data:
09/536.235
27 March 2000 (27.03.2000) US
(71) Applicant: USF FILTRATION AND SEPARATIONS
GROUP, INC. [US/US]; 21 18 Creenspring Drive, Timo-
nium, MD 21093 (US).
(72) Inventors: HODGES, Alastair, Mclndoe; 11752 West-
view Paiicway, Apartment 6, San Diego. CA 92126 (US).
CHATELIER, Ron; 11816 Westview Parkway. Apart-
ment 174. San Diego, CA 92126 (US). CHAMBERS,
Garry; 11782 Westview Parkway, Apartment 84, San
Diego. CA 92126 (US).
(74) Agent: ALTMAN, Daniel, E.; Knobbe, Martens, Olson &
Bear, LLP, 620 Newport Center Drive, 1 6th Floor, Newport
Beach, CA 92660 (US).
(81) Designated States (national): AE, AG, AL, AM, AT, AU,
AZ, BA. BB. BG, BR, BY, BZ, CA. CH, CN, CR. CU. CZ.
CZ (utility model), DE, DE (utility model), DK. DK (utility
model), DM, DZ, EE, EE (utility model), ES, Fl, Fl (utility
model). GB, GD, GE, GH, GM, HR, HU. ID. IL, IN, IS, JP.
KE, KG, KP. KR. KZ, LC. LK, LR, LS. LT, LU. LV, MA.
MD. MG. MK, MN. MW. MX. MZ. NO. NZ, PL, PT. RO.
RU. SD. SE, SG. SI, SK, SK (utility model). SL. TJ. TM.
TR, TT, TZ. UA, UG. UZ, VN. YU. ZA, ZW.
(84) Designated States (regional): ARIPO patent (GH, GM,
KE, LS. MW, MZ, SD, SL, SZ. TZ, UG, ZW), Eurasian
patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
patent (AT, BE, CH. CY. DE, DK, ES. R. FR, GB, GR, IE.
nr. LU, MC. NL. PT. SE, TR), OAPl patent (BF, BJ, CP.
CG. a. CM, GA, GN, GW, ML. MR, NE, SN. TD, TG).
Published:
— with international search report
— before the expiration of the time limit for amending the
claims and to be republished in the event of receipt of
amendments
For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations " appearing at the begin"
ning of each regular issue of the PCT Gazette.
(54) Title: METHOD AND DEVICE FOR SAMPUNG AND ANALYZING INTERSmiAL FLUID AND WHOLE BLOOD
SAMPLES
(57) Abstract: The invention disclosed in this application is a method and device (10) for combin-
ing the sampling and analyzing of sub-dermal fluid samples, e.g.. interstitial fluid or whole blood,
in a device suitable for hospital bedside and home use. The device includes a dermal layer pen-
etration probe (12) in fluid communication with an analysis chamber (20). It is applicable to any
analyte that exists in a usefully representative concentration in the fluid, and is especially suited to
the monitoring of glucose.
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METHOD AND DEVICE FOR SAMPLING AND ANALYZING
INTERSTITIAL FLUID AND WHOLE BLOOD SAMPLES
Field of the Invention
The present invention relates to a method and device for combining the sampling and analyzing of interstitial
fluid or whole blood samples which is suitable for hospital bedside and home use.
Background of the Invention
The management of many medical conditions requires the measurement and monitoring of a variety of
analytes in bodily fluid. Historically, the measurement of anaiytes in blood has required an invasive technique, such as
a venipuncture or finger puncture, to obtain blood for sampling purposes. An example of an analyte which is routinely
tested by obtaining a blood sample through an invasive technique is glucose. In order to control their condition,
diabetics must monitor their glucose levels on a regular basis. Invasive techniques used to obtain a blood sample for
analysis have the disadvantage of being painful, which can reduce patient compliance In regular monitoring. Repeated
testing, e.g., on a fiogertip, can result in scar tissue build-up which makes obtaining a sample in that region more
difficult. Moreover, invasive sampling procedures pose a risk of infection or disease transmission.
An alternative is to sample interstitial fluid rather than whole blood, interstitial fluid is the fluid that fills the
space between the connective tissue and cells of the dermal layer of the skin. An application where interstitial fluid
has been shown to be an appropriate sampling substitute for plasma or whole blood Is in the measurement of glucose
concentration (J. Lab. Clin. Med. 1997, 130, 436-41).
In the patents US 5,879,367, US 5,879,310, US 5,820,570 and US 5,582,184 are disclosed methods of
sampling using a fine needle in conjunction with a device to limit the penetration depth to obtain small volumes of
interstitial fluid for the purpose of glucose monitoring. However, there is no method disclosed for analyzing the drawn
samples that is suitable for home use or hospital bedside use.
Summary of the Invention
It is desirable to be able to measure the concentration of analytes in humans or other animals without having
to draw a blood sample by conventional methods. It is further desirable to be able to do so with an inexpensive
disposable device that is simple enough for home or hospital bedside use.
The invention provides a suitable alternative to conventional sampling devices and methods that is less
invasive than traditional whole blood sampling techniques and that requires a considerably smaller sample volume than
is required in the conventional venipuncture or finger puncture sampling methods. Because of the smaller sample
volume required, a smaller wound is necessary to obtain the sample. In the conventional finger stick method, a drop of
blood is fonned on the tip of a finger, then the sensor sample entrance is wetted with the drop. Because the sample
comes into contact with the skin surface, contamination of the sample by material on the skin surface is possible. The
devices and methods disclosed herein do not require forming a blood drop on the surface of the skin, and therefore
have less risk of sample contamination.
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In one embodiment of the present invention, a fluid sampling device is provided which includes a body, the
body induding a dermal layer penetration probe having a penetrating end and a communicating end, and an analysis
cfiamber having a proximal and distal end, the analysts chamber having a volume, wherein the penetration probe is in
fluid communication with the analysis chamber such that fluid can flow from the penetration probe toward the
analysis chamber. The analysis chamber can have at least one flexible wall which can be compressed to reduce the
volume of the analysis chamber. The penetration probe can include, for example, a needle, a lancet a tube, a channel,
or a solid protrusion and can be constructed of a material such as carbon fiber, boron fiber, plastic, metal, glass,
ceramic, a composite material, mixtures thereof, and combinations thereof. The penetration probe can include two
sheets of material in substantial registration, having a protrusion on each sheet wherein the sheets are spaced apart
such that liquid can be drawn between the sheets by capillary action. The two sheets of material can extend into the
device so as to form a pre*chamber. The penetration probe can be positioned within a recess in the proximal end of the
device, and the recess can be configured to substantially align with a shape of a selected dermal surface.
In a further embodiment the device can further include a pre-chamber having a volume and a first and second
end, wherein the pre-chamber Is interposed between the penetration probe and the analysis chamber such that the first
end of the pre>chamber is adjacent the cGmmunicating end of the penetration probe and the second end of the pre-
chamber is adjacent the proximal end of the analysis chamber. The volume of the pre-chamber can be greater than or
equal to the volume of the analysis chamber. The pre-chamber can have at least one flexible wall that can be
compressed to reduce the volume of the prfrdiamber. The pre-chamber can also include a valve at the first end
capable of substantially sealing the pre-chamber from the penetration probe.
In another embodiment, the device further includes a compressible bladder in communication with the
analysis chamber, the compressible bladder being capable of applying a positive or a negative pressure to the analysis
chamber.
In yet another embodiment the pre-chamber and the analysis chamber can be capable of exerting different
capillary forces. The capillary force exerted by the analysis chamber can be greater than the capillary force exerted by
the pre-chamber. The differential capillary force can be derived, at least in part, from a difference between the pre-
chamber height and the analysis chamber height In this embodiment the interior surface of the pre-chamber can
Include at least first and second pre-chanrtber walls spaced apart at a first distance to define a pre-chamber height, and
the interior surface of the analysis chamber can include at least first and second analysis chamber walls spaced apart
at a second distance to define an analysis chamber height wherein the height of the analysis chamber is less than the
height of the pre-chamber.
In yet another further embodiment at least one of the chambers can include a substance capable of
enhancing or diminishing the capillary force exerted by the chamber. The substance can include, for example, a
polymer, a resin, a powder, a mesh, a fibrous material, a crystalline material, or a porous material. Suitable substances
include polyethylene glycol, polyvinylpyrrolidone, a surfactant a hydrophilic block copolymer, and polyvinyiacetate.
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In a further embodiment the device further includes a releasable actuator capable of supplying a force
sufficient to cause the penetration probe to penetrate a dermal layer. The actuator can be external to or integral with
the body, and upon release propels the body toward the dermal layer.
In a further embodiment, the analysis chamber can include an electrochemical cell including a working
5 electrode and a counter/reference electrode and an interface for communication with a meter, wherein the interface
communicates a voltage or a current.
In yet another embodiment of the present invention, a method for determining a presence or an absence of an
analyte in a fluid sample is provided including the steps of providing a fluid sampling device as described above;
penetrating a dermal layer with the penetration probe; sybstantially filling the analysis chamber with a fluid sample by
10 allowing the sample to flow from the penetration probe toward the analysis chamber; and detecting a presence or an
absence of the analyte within the analysis chamber. The sample can include, for example, interstitial fluid and whole .
blood. A qualitative or quantitative measurement of a characteristic of the sample can be obtained in the detecting
step. The characteristic of the sample can include, for example, a reaction product of the analyte, such as a color
indicator, an electric current, an electric potential, an acid, a base, a reduced species, a precipitate, and a gas. The
15 analyte can include, for example, an ion such as potassium, an element, a sugar, an alcohol such as ethanol, a
hormone, a protein, an enzyme, a cofactor, a nucleic acid sequence, a lipid, a pharmaceutical, and a drug. Cholesterol
and lactate are examples of substances that can be analyzed.
In a further embodiment, the flow of sample toward the analysis chamber can be driven by a driving force,
e.g., capillary force or a pressure differential. Where the analysis chamber has a flexible wall, the wall can be
20 compressed to reduce the volume of the analysis chamber prior to penetrating the dermal, then the compression
released to form a partial vacuum in the analysis chamber. Where the fluid sampling device further includes a
compressible bladder, the bladder can be compressed to reduce its volume, then after penetration of the dermal layer
the compression can be released to form a partial vacuum in the compressible bladder and analysis chamber.
Brief Description of the Drawinns
25 FIG. 1 shows a top view (not to scale) of one embodiment of a sampling device illustrating an arrangement of
. the penetration probe, pre-chamber, and analysis chamber.
FIG. 2 shows a cross section (not to scale) along the line A-A' of FIG. 1.
FIG. 3 shows a top view (not to scale) of one embodiment of a sampling device illustrating an arrangement of
the penetration probe, pre-chamber, and analysis chamber wherein the proximal edge of the device forms a recess.
30 FIG. 4 shows a top view (not to scale) of one embodiment of a sampling device illustrating an arrangement
of the penetration probe, pre-chamber, and analysis chamber,
FIG. 5 shows a cross section (not to scale) along the line B-B' of FIG. 4.
FIGS. 6a and 6b (not to scale) depict an embodiment of the invention wherein the device is loaded in a
releasable actuator to facilitate penetration of a dermal layer by the penetration probe. Fig. 6a depicts the device
3.
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loaded in the actuator, wherein the actuator is in the cockwl position, ready to be triggered. Fig. 6b depicts the device
and actuator after triggering.
Dctail9d Description of the Preferred Embodiments
Introduction
S The following description and examples illustrate various embodiments of the present invention in detafl.
Those of skill in the art will recognize that there are numerous variations and modifications of this invention that are
encompassed by its scope. Accordingly, the description of a preferred embodiment should not be deemed to limit the
scope of the present invention. Methods and devices for optimizing sampling of fluid samples are discussed further in
copending U.S. patent application no _/ , filed on even date herewith, entitled "METHOD OF
10 PREVENTIWG SHORT SAMPLING OF A CAPILLARY OR WICKING FILL DEVICE," which is incorporated herein by
reference in its entirety.
The invention disclosed in this application is a method and device for combining the sampling and analyzing of
a fluid sample from sub-dermal tissue in a device suitable for hospital bedside and home use. The fluid sample can
comprise, but is not limited to, interstitial fluid or whole blood samples obtained from an animal Any fluid sample
15 obtained from sub-dermal tissue of a plant or an animal can sampled and analyzed, thus the invention has broad
application in the fields of human medicine, veterinary medicine, and horticultural science. The device and method are
applicable to any analyte that exists in a usefully representatwe concentration in the fluid sample. For clarity, the
present disclosure will discuss the application to glucose monitoring. However, it is to be understood that the
invention is not limited to the monitoring of glucose, and that other analytes, as discussed below, can also be
20 measured.
The method utilizes an integrated sampling and analyzing device 10 incorporating a penetration probe 12
capable of penetrating a patient's dermal layers to extract an interstitial fluid or whole blood sample, and a method for
transferring the sample from the penetration probe 12 to the analysis chamber 20. In one embodiment, the device 12
can be a one-shot disposable device which can be inserted into a meter which communicates with the analysis
25 chamber 20 to perform the analysis of the sample and present and optionally store the result.
In the device 10, a penetration probe 12 for penetrating the subject's dermal layers to collect an interstitial
fluid or whole blood sample is integrated with an analysis chamber 20. A property of sampling interstitial fluid is that
it can take from several to tens of seconds to collect sufficient sample to analyze. This is often not desirable for an
analysis chamber 20 wherein the analyte undergoes a reaction as part of the analysis process, as it can be difficult to
30 obtain an accurate start time for the test as well as achieve an even reacting reagent distribution in the sample. In a
second aspect of the current invention a method is disclosed for collecting the sample in a pre-chamber 14 and, when
fuH, transferring the sample quickly to an analysis chamber 20.
In this disclosure, unless a different meaning is clear from the context of its usage, "proximal" refers to a
region or structure of the device situated toward or adjacent to the dermal surface to be penetrated, and "distal"
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refers a region or structure of the device situated toward the opposite (non-proximai) end of the device. For example,
the penetration probe 1 2 is at the proximal end of the device.
The Penetration Probe
The penetration probe 12 can be any device capable of penetrating the patient's dermal layers to the desired
5 extent and capable of transporting a sample to a pre-chamber 14 or analysis chamber 20. The penetration probe 12
comprises two ends, as illustrated in FIG. 1. The penetrating end 1 1 of the penetration probe 12 is the end inserted
Into the dermal layer. The communicating end 13 of the penetration probe 12 is the end which is in communication
with either the pre-chamber 14 or the analysis chamber 20.
One or more protrusions 12 with at least one sharp edge or point are suitable as the penetration probe 12.
10 The penetration probe 12 can be fabricated from materials including plastic, metat glass, ceramic, a composite
material (e.g., a composite of ceramic and metal particles), or mixtures and combinations of these materials. The
penetration probe 12 can be in the form of a solid protrusion, a needle, a lancet, a tube or a channel. The channel can
optionally be open along one or more of its elongated sides. As illustrated in FIG. 2, a preferred embodiment of the
penetration probe 12 is two sheets 30 of material formed so as to have a sharply pointed protrusion 12 on each sheet
15 30 in substantial registration, with the sheets 30 spaced apart such that liquid can be drawn between the sheets 30
by capillary action. In a particularly preferred embodiment the two sheets 30 of material extend to and overlap with
the analysis chamber 20 to form a pre-chamber 14 for sample collection.
When interstitial fluid is sampled, the penetration depth can be controlled by limiting the length the
penetration probe 12 protrudes from the proximal surface 34 of the sampling device 10 to less than the thickness of
20 the dermal layer. In a preferred embodiment, the length of the protrusion 12 will be less than 2 to 3 mm, more
preferably about 1.5 mm. After penetration to a suitable depth corresponding to the length of the protrusion 12,
contact between the surface of the dermal layer and the surface 34 of the analyzing device prevents further
penetration. For other uses, such as in sampling interstitial fluid from regions having a thick dermal layer, or for
veterinary uses, it can be desirable for the length of the protrusion 12 to be greater than 3 mm. Accordingly, the
25 invention contemplates protrusions 12 of any length, wherein the length is sufficient to sample interstitial fluid. When
whole blood is sampled, a slightly longer penetration probe 12 should be used, i.e., one having a length greater than 2
to 3 mm.
The diameter or width of the penetration probe 12 depends upon the design of the penetration probe 12.
Suitable diameters or widths are those which provide sufficient sample flow. In the case of a protrusion 12 forming a
30 sharp edge or point, or a tube or channel, the minimum diameter or width is typically greater than about lOpjn. When
the penetrating means 12 comprises two sheets 30 in substantial registration, each having a sharply pointed
protrusion 12, the two protrusions 12 are typically spaced from 1 mm to 10 ^m apart.
The penetration probe 12 can be located on any suitable part of the test strip 10, i.e., an edge 34, a comer
42, or one of the flat surfaces 44. Protection can be provided to the penetration probe 12 by locating it within a
35 recess formed in the distal edge 34 of the test strip ID, as shown in FIG. 3, or in a depression on the surface 44 of the
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test strip 10. In a preferred embodiment the recess in the distal edge 34 of the test strip 10 can be configured to
substantially align with the shape of a selected dermal surface, e.g., a fingertip. However, the recess can be
configured in other suitable shapes, e.g., a square recess, a V-shaped recess, a curved recess, a polygonal recess, and
the like. In a preferred embodiment, the penetration probe 1 2 does not protrude past the proximal-most portion of the
proximal edge 34 or surface 44 of the device 10, but when pressed against the skin, the skin deforms into the recess
and is punctured by the penetration probe 12. Such an arrangement aids sampling by compressing the area of the skin
around the sampling point. The penetration probe 12 can fomn an integral part of another component of the test strip
10, e.g., a side of the pre-chamber 54, as shown in FIG. 2. Alternatively, the penetration probe 12 can comprise a
separate part which is attached to or incorporated into the test strip 10 by any suitable means, e.g., adhesive, thermal
bonding, interlocking parts, pressure, and the like. The penetration probe 12 can be retractable or non-retractable.
Penetration itself can be accomplished by any suitable means, including inserting the penetration device 12
manually or by means of a releasable actuator 84 such as, for example, a spring-loaded mechanism 84 as depicted in
FIGS. 6a and 6b. Such a spring-loaded mechanism 84 incorporates a spring 86 which is compressed and held in place
by a trigger 88 which can release the force compressing the spring 86 when the triggering mechanism is activated.
The trigger 88 can be activated manually, or the device 84 can incorporate a pressure sensor which indicates that
sufficient pressure has been applied to obtain the sample, thereby activating the trigger 88. In one embodiment, the
distal end of the device 10 is placed in the spring-loaded mechanism 84 such that when the force compressing the
spring 86 is released by acth^ating the trigger 88, force is transferred to the device 10, which is ejected from the
mechanism 84, thereby inserting the penetrating probe 12 into the dermal layer.
Any suitable body part can be used for sampling. In a preferred embodiment, the sampling area is one which
does not have a high density of nerve endings, e.g., the forearm. Typically, 5 to 15 seconds is required to obtain
sufficient sample. Application of pressure to the sampling area can be needed to extract interstitial fluid or whole
blood. To facilitate the appropriate amount of pressure being applied, a pressure sensor can be incorporated into the
device 10 which indicates when sufficient pressure has been applied. Sample acquisition time can be improved by
applying increased pressure to the area surrounding the direct sampling area. Some of the factors that can affect
interstitial fluid or whole blood sample acquisition include the patient's age, skin thickness, temperature, and
hydration. The amount of interstitial or whole blood sample collected for testing can preferably be about 0.02^1 or
greater, more preferably 0.1 or greater, and most preferably about 0.5p,l or greater.
In one preferred embodiment, the device 10 can be inserted into a meter prior to sample acquisition. In such
an embodiment, the meter serves multiple functions, including supporting the device 10, providing an automated means
of initiating sample acquisition, and indicating when sample acquisition is complete.
Transfer of Sample from Penetration probe to Analysis Chamber
In a preferred embodiment of the sampling device 10, the device comprises two parts - the penetration probe
12 and an analysis chamber 20. In another preferred embodiment, illustrated in FIGS. 1 and 2, the device 10
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comprises the penetration probe 12 and a pre-chamber 14. The pre-chamber 14 can then be integrated with or can be
interfaced to the analysis chamber 2Q.
In a further embodiment, the analysis chamber 20 is Integrated with or can be interfaced to a means for
facilitating filling of the analysis chamber 20. This means can comprise a collapsible or compressible bladder 22, as
5 shown in FIGS. 3 and 4, which can be used to apply a positive or negative pressure (i.e., partial vacuum) to the analysis
chamber 20. The compressible bladder 22 can comprise any chamber with flexible walls that can be compressed to
reduce the volume of the chamber. When the force compressing the compressible bladder 22 is released, a partial
vacuum is formed which draws sample into the analysis chamber 20. In a preferred embodiment, the volume of the
coiT^ressible bladder 22 is sufficiently large so that when the bladder 22 is substantially fully compressed, the
iO reduction in volume of the bladder 22 is larger than or equal to the total volume of the analysis chamber 20, thereby
ensuring that the analysis chamber 20 is substantially filled. However, a compressible bladder 22 with a smaller
volume than the analysis chamber 20 can also be effective in assisting the filling of the analysis chamber 20.
Alternatively, the analysis chamber 20 itself can be collapsible or compressible. In such an embodiment, a
piston or other compressing agent such as a patient's or clinician's fingers, can first compress then release the
15 analysis chamber 20, thereby forming a partial vacuum. When the compressing force is released, the partial vacuum
causes the sample to flow from the penetration probe toward the analysis chamber.
Pre-chamber
In a preferred embodimem, as illustrated in FIGS. 1 and 2, a pre-chamber 14 is provided in the integrated
sampling and testing device 10 for accumulation and storage of the collected sample prior to its being transferred to
20 . the analysis chamber 20. A pre-chamber 14 is useful when using an analysis method which requires that the sample
fill the analysis chamber 20 in a short period of time to return accurate results, I.e., a time shorter than that required
to draw sufficient sample from the dermal layer. In a preferred embodiment, the volume of the pre-chamber 14 is
larger than that of the analysis chamber 20, thus ensuring that once the pre-chamber 1 4 is filled, sufficient sample has
been collected to completely fill the analysis chamber 20.
25 In a preferred embodiment, as illustrated in FIGS. 1 and 2, the penetration probe 12 opens into the pre-
chamber 14 at a first end, and at the second end the pre-chamber 14 opens to the analysis chamber 20. The pre-
chamber 14 can be free of reagents or other substances, or can optionally contain one or more substances to enhance
or diminish the capillary force exerted by the walls of the pre-chamber 14 or to pre-treat the sample prior to analysis.
These substances can include, for example, polymers, resins, powders, meshes, fibrous materials, crystalline materials,
30 porous materials, or a mixture or combination thereof. To facilitate effective filling of the analysis chamber 20, a
preferred embodiment utilizes a pre-chamber 14 and analysis chamber 20 of different heights, as shown in FIG. 2.
Where the analysis chamber 20 is formed so that its height (typically referring to the smallest chamber dimension) is
smaller than the height of the pre-chamber 1 4, a capillary force is generated that is capable of drawing fluid out of the
pre-chamber 14 and into the analysis chamber 20. A first air vent 64 can be formed at the end 70 of the analysis
35 chamber 20 opposite the opening 62 to the pre-chamber 14, facilitating the filling of the analysis chamber 20 by
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aUowing atr to be displaced from the analysis chamber 20 as sample enters. Optionally, a second vent 74 can be
fomied opening into the pre-chamher 14 at the substantially opposite end 60 of the pre-chamber 14 to where the
penetration probe 12 opens into the pre chamber 14. This vent 74 provides air to the pre-chamber 14 to replace the
sample as it is transferred from the pre-chamber 14 to the analysis chamber 20. The vent 74 can be placed in any
5 suitable position on the test strip 10. In a preferred embodiment, the vent 74 incorporates a sharp corner, e.g., at a
90** angle, which functions as a "capillary stop" to prevent sample from exiting the device 10 through the vent 74.
In another embodiment, the pre-chamber 14 consists of a tube, or other shaped chamber, with flexible walls,
attached to the penetration probe 12. In this embodiment, the pre-chamber 14 is either permanently fixed to the
analysis chamber 20 or is placed next to and aligned with a port to the analysis chamber 20. Such alignment can
1 0 occur during use by suitable placement in an external device such as the measurement meter. In one aspect of this
embodiment, the pre-chamber 14 further comprises a valve, defined as a device to control the flow of fluid sample
between the penetration probe 12 and the pre-chamber 14. The valve can comprise one or more rollers, pistons, or
squeezing devices capable of simultaneously closing off the first end 60 of the pre-chamber 14, and compressing the
pre-chamber 14 such that the fluid in the pre-chamber 14 is forced towards the second end 62 of the pre-chamber 14
1 5 and subsequently into the analysis chamber 20.
Alternatively, the analysis chamber 20 consists of a tube, or other shaped chamber, with flexible wails,
attached to the penetration probe 12. In one aspect of this embodiment, the analysis chamber 20. prior to
penetration, is compressed by one or more rollers, pistons, or other squeezing devices. After the penetration probe 12
is inserted, the compression is released, forming a vacuum which pulls sample into the analysis chamber 20. In such
20 an embodiment the pre-chamber 14 can not be necessary if sufficient vacuum is generated for rapid sample
acquisition. In such an embodiment, the device 10 can not require a vent 64, 74 if such would interfere with forming
. a vacuum.
In another embodiment illustrated in FIGS. 3 and 4, a pre-chamber 14 of suitable size is formed which opens
to the penetration probe 12 on one end 60 and to the analysis chamber 20 on the other end 62. The end 70 of the
25 analysis chamber 20 opposite to that opening to the pre-chamber 14 opens to a compressible bladder 22. The bladder
22 can be formed separately and attached to the end 70 of the analysis chamber 20. Alternatively, it can be formed
by removing a section on the middle laminate 82 in the test strip 10, similar to those described in W097/00441
(incorporated herein by reference in its entirety), as illustrated in FIGS. 3 and 4.
In use, the bladder 22 in the strip 10 is compressed by suitable means prior to the penetration probe 12
30 being inserted into the patient. Insertion of the penetration probe 12 can be confirmed by use of a sensor, such as a
pressure sensor, or the patient can confirm that the penetration probe 12 Is inserted either visually or by touch. In the
latter case, the patient sensing can signal the meter, such as by pushing a button. At this point, the means
compressing the bladder 22 is withdrawn to a halfway position to draw sample into the pre-chamber 14. When the
pre-chamber 14 is full, as indicated by a suitable sensor, the meter indicates to the patient to withdraw the
35 penetration probe 12. The compressing means then moves to its fully withdrawn position and so draws the sample
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from the pre-chamber 14 into the analysis chamber 20. In the case where the initial suction from the bladder 22
causes the sample to be accumulated with sufficient speed, the pre-chamber 14 can be dispensed with and the bladder
22 used to draw sample through the penetration probe 12 directly into the analysis chamber 20. A vent 64, 74 which
would interfere with forming a vacuum need not be incorporated into the device in some embodiments.
5 Analysis Chamber
In a preferred embodiment, the analysis chamber 20 is contained in an analyzing device 10 comprising a
disposable analysis strip similar to that disclosed in W097/00441. The analysis strip of WQ97;00441 contains a
biosensor for detennining the concentration of an analyte in a carrier, e.g., the concentration of glucose in a fluid
sample. The electrochemical analysis cell 20 in this strip has an effective volume of I.Sfil or less, and can comprise a
10 porous membrane, a working electrode on one side of the membrane, and a counter/reference electrode on the other
side. In a preferred embodiment, an analysis cell 20 having an effective volume of about 0.02fii or greater is used.
More preferably, the cell 20 has a volume ranging from about 0.1 p.1 to about 0.5^1.
In one aspect of this embodiment, the penetration probe 12 is a small needle integrated into the analysis
strip 10 by being inserted through a wall of the analysis chamber 20 such that one end of the needle 12 opens into the
15 strip analysis chamber 20. In using a device 10 having this arrangement to obtain and analyze a sample of interstitial
fluid, the needle 12 is inserted into the patient's dermal layer and sample is drawn into the needle 12 via capillary
action. The sample is then transferred from the needle 12 into the analysis chamber 20 by capillary action whereupon
the sample is analyzed. An opening 64 in the analysis chamber 20 to atmosphere, remote from the point where the
needle 12 opens into the chamber, acts as a vent 64 to allow the escape of displaced air as the analysis chamber 20
20 fills with sample. Analysis devices of the type disclosed in W097/00441 are particularly suited for use with this
arrangement because of their ability to utiDze the very small volumes of sample typically available with interstitial fluid
sampling.
The analysis chamber 20 can contain one or more substances to enhance or diminish the capillary force
exerted by the walls of analysis chamber 20. Such materials can include polymers, resins, powders, meshes, fibrous
25 materials, crystalline materials, porous materials, or a mixture or combination thereof, as can also be used in the pre-
chamber, discussed above. For example, the walls 24 of the analysis chamber 20 can be coated with a hydrophilic
material to encourage the flow of fluid sample into the analysis chamber. Suitable hydrophilic materials include
polyethylene glycol, polyvinylpyrrolidone, a surfactant, a hydrophilic block copolymer, and polyacrylic acid. The
analysis chamber 20 can also contain reagents capable of reacting with the analyte or other substances present in the
3Q sample. Such other substances can include substances which interfere in determining the presence or absence of the
analyte. In such cases, the reagent will react with the substance so that it no longer interferes with the analysis.
Any analyte present in a fluid sample in a detectable amount can be analyzed using the device 10. A typical
analytes can include, but is not limited to, an ion, an element, a sugar, an alcohol, a hormone, a protein, an enzyme, a
cofactor, a nucleic acid sequence, a lipid, and a drug. In a preferred embodiment, glucose is the analyte to be tested.
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Typical analytes could include, but are not limited to, ethanoL potassium ion phamiaceuticals, drugs. Cholesterol and
lactate.
The presence or absence of the analyte can be determined directly. Alternatively, the analyte can be
determined by reacting the analyte with one or more reagents present in the analysis chamber. The product of that
5 reaction, indicative of the presence or absence of the analyte^ vvould then be detected. Suitable reaction products
include, but are not limited to, a color indicator, an electric current, an electric potential, an acid, a base, a precipitate,
or a gas.
Any suitable analytical method can be used for determining the presence or absence of the analyte or a
reaction product of the analyte. Suitable analytical methods include, but are not limited to, electrochemical methods,
10 photoabsorption detection methods, photoemission detection methods, and the measurement of magnetic
susceptibility. In the case of a reaction product having a different color than the analyte, or the formation of a
precipitate or a gas, a visual determination can be a suitable method for determining the presence or absence of the
analyte.
Displav/Storane of Measurement Data
IS In a preferred embodiment, an analysis strip as described above or another embodiment of the sampling
device 10 is integrated with a measuring device, e.g.. a meter, which can display, store or record test data, optionally
in computer-readable format. In such an embodiment, the test strip 10 comprises an interface for communicating with
the meter, e.g., conductive leads from the electrodes of the electrochemical cell 20. In the case of obtaining an
electrochemical measurement the interface communicates a voltage or a current to the electrochemical cell 20.
20 The above description discloses several methods and materials of the present invention. This invention is
susceptible to modifications in the methods and materials, as well as alterations in the fabrication methods and
equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure
or practice of the invention disclosed herein. Consequently, it is not intended that this invention be limited to the
specific embodiments disclosed hereia but that it cover all modifications and alternatives coming within the true scope
25 and spirit of the Invention as embodied in the attached claims.
.10.
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WHAT IS CLAIMED IS:
1. A fluid sampling device comprising a body, the body comprising a dermal layer penetration probe having a
penetrating end and a communicating end, and an analysis chamber having a proximal and distal end. the analysis
chamber having a volume, wherein the penetration probe is in fluid communication with the analysis chamber such that
5 fiuid can flow from the penetration probe toward the analysis chamber.
2. The device of claim 1, wherein the analysis chamber has at least one flexible wall and wherein upon
compression of the chamber at the flexible wall the volume of the analysis chamber is reduced.
3. The device of claim 1 . further comprising a pre-chamber having a volume and a first and second end, wherein
the pre-chamber is interposed between the penetration probe and the analysis chamber such that the first end of the
10 pre-chamber is adjacent the communicating end of the penetration probe and the second end of the pre-chamber is
adjacent the proximal end of the analysis chamber.
4. The device of claim 3. wherein the volume of the pre-chamber is greater than or equal to the volume of the
analysis chamber. •
5. The device of claim 3, wherein the pre-chamber has at least one flexible wall and wherein upon compression
15 of the chamber at the flexible wall the volume of the pre-chamber is reduced.
6. The device of claim 3, wherein the pre-chamber comprises a valve at the first end capable of substantially
sealing the pre-chamber from the penetration probe.
7. The device of claim 3, wherein the pre-chamber is capable of exerting a first capillary force and the analysis
chamber is capable of exerting a second capillary force and wherein a differential exists between the first and the
20 second capillary forces.
8. The device of claim 1, wherein the capillary force exerted by the analysis chamber is greater than the
capillary force exerted by the pre-chamber.
9. The device of claim 8, wherein an interior surface of the pre-chamber comprises at least first and second pre-
chamber walls spaced apart at a first distance to define a pre-chamber height, and wherein an interior surface of the
25 analysis chamber comprises at least first and second analysis chamber wails spaced apart at a second distance to
define an analysis chamber height, wherein the height of the analysis chamber is less than the height of the pre-
chamber, and wherein the differential capillary force derives at least in part from a difference between the pre-
chamber height and the analysis chamber height.
10. The device of claim 7, wherein at least one of the chambers comprises a substance capable of enhancing or
30 diminishing the capillary force exerted by the chamber.
11. The device of claim 10, wherein the substance is selected from the group consisting of a polymer, a resin, a
powder, a mesh, a fibrous material, a crystalline material, a porous material, or a combination thereof.
12. The device of claim 10, wherein the substance is selected from the group consisting of polyethylene glycol,
polyvinylpyrrolidone, a surfactant, a hydrophilic block copolymer, and polyvinylacetate.
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1 3. The device of claim 3, wherein the pre-chamber comprises a first pre-chamber wall and a second pre chamber
wall and wherein the analysis chamber comprises a first analysis chamber wall and a second analysis chamber wail,
and wherein the distance between the pre chamber walls is greater than the distance between the analysis chamber
walls.
5 14. The device of claim 1. further comprising a compressible bladder in communication with the analysis
chamber, the compressible bladder being capable of applying a positive or a negative pressure to the analysis chamber.
15. The device of claim 14, wherein the compressible bladder opens into the distal end of the analysis chamber.
16. The device of claim 1, wherein the penetration probe is selected from the group consisting of a needle, a
lancet, a tube, a channel, and a solid protrusion.
10 17, The device of claim 1 , wherein the penetration probe comprises a material selected from the group consisting
of carbon fiber, boron fiber, plastic, metal, glass, ceramic, a composite material, mixtures thereof, and combinations
thereof.
18. The devicaof claim 1, wherein the penetration probe comprises two sheets of material in substantial
registration, having a protrusion on each sheet, wherein the sheets are spaced apart such that liquid can be drawn
1 5 between the sheets by capillary action.
19. The device of claim 18, wherein the two sheets of material extend into the device so as to form a pre-
chamber adjacent the analysis chamber and in fluid communication therewith.
20. The device of claim 1, wherein the device has a proximal edge, the edge comprising a recess, wherein the
penetration probe is positioned within the recess.
20 21. The device of claim 20, wherein the recess is configured to substantially align with a shape of a selected
dermal surface.
22. The device of claim 1 , further comprising a releasable actuator, wherein the actuator is capable of supplying
a force sufficient to cause the penetration probe to penetrate a dermal layer.
23. The device of claim 22, wherein the actuator is external to the body, and wherein upon release the actuator
25 propels the body toward the dermal layer.
24. The device of claim 22, wherein the actuator Is integral with the body.
25. The device of claim 24, wherein upon release the actuator propels the penetration probe toward the dermal
layer.
26. The device of claim 1 , wherein the analysis chamber comprises an electrochemical ceil, the cell comprising a
30 working electrode and a counter/reference electrode.
27. The device of claim 1 , further comprising an interface for communication with a meter.
28. The device of claim 28, wherein the interface communicates a voltage or a current.
29. A method for determining a presence or an absence of an analyte in a fluid sample comprising the steps of:
providing a fluid sampling device comprising a demfial layer penetration probe having a penetrating end and a
35 communicating end, and an analysis chamber having a proximal and distal end, the analysis chamber having a volume,
•12-
wo 01/72220 PCT/USOl/09673
wherein the penetration probe is in fluid communication with the analysis chamber such that fluid can flow from the
penetration probe toward the analysis chamber;
penetrating a dermal layer with the penetration probe;
substantially filling the analysis chamber with a fluid sample by allowing the sample to flow from the
5 penetration probe toward the analysis chamber; and
detecting a presence or an absence of the analyte within the analysis chamber.
30. The method of claim 29, wherein the sample is selected from the group consisting of interstitial fluid and
whole blood.
31. The method of claim 29, wherein the detecting step comprises a qualitative or quantitative measurement of a
1 0 characteristic of the sample.
32. The method of claim 31 wherein the characteristic of the sample comprises a reaction product of the
analyte.
33. The method of claim 32, wherein the reaction product is selected from the group consisting of a color
indicator, an electric current, an electric potential, an acid, a base, a precipitate, and a gas.
15 34. The method of claim 29, wherein the analyte is selected from the group consisting of an ion, an element, a
sugar, an alcohol, a hormone, a protein, an enzyme, a cofactor, a nucleic acid sequence, a lipid, a pharmaceutical, and a
dnig.
35. The method of claim 29, wherein the analyte is selected from the group consisting of potassium ion, ethanol,
cholesterol, and lactate.
20 36. The method of claim 29, wherein the flow of sample toward the analysis chamber is driven by a driving
force, wherein the driving force comprises a force selected from the group consisting of a capillary force and a
pressure differential.
37. The method of claim 29, the fluid sampling device further comprising a pre chamber having a volume and a
first and second end, wherein the pre-chamber is interposed between the penetration probe and the analysis chamber
25 such that the first end of the pre chamber is adjacent the communicating end of the penetration probe and the second
end of the pre-chamber is adjacent the proximal end of the analysis chamber.
38. The method of claim 37, wherein the pre-chamber is capable of exerting a first capillary force and the
analysis chamber is capable of exerting a second capillary force and wherein a differential exists between the first and
the second capillary forces.
30 .39. The method of claim 38, wherein the capillary force exerted by the analysis chamber is greater than the
capillary force exerted by the pre-chamber.
40. The method of claim 39, wherein an interior surface of the pre-chamber comprises at least first and second
pre-chamber walls spaced apart at a first distance to define a pre-chamber height, and wherein an interior surface of
the analysis chamber comprises at least first and second analysis chamber walls spaced apart at a second distance to
35 define an analysis chamber height, wherein the height of the analysis chamber is less than the height of the pre-
.13.
wo 01/72220 PCT/USOl/09673
Chamber, and wherein the differentia! capillary force derives at least in part from a difference between the pre-
chamber height and the analysis chamber height.
41. The method of claim 39, wherein at least one of the chambers comprises a substance capable of enhancing
or diminishing the capillary force exerted by the chamber.
5 42. The method of claim 41, wherein the substance is selected from the group consisting of a polymer, a resin, a
powder, a mesh, a fibrous mataial. a crystalline material, a porous material, or a combination tfiereof.
43. The method of claim 41, wherein the substance is selected from the group consisting of polyethylene glycol,
polyvinylpyrrolidone, a surfactant a hydrophilic block copolymer, and polyacrylic acid.
44. The method of claim 38, wherein the pressure differential comprises a positive pressure applied toward the
10 analysis chamber.
45. The method of claim 36, wherein the pressure differential comprises a negative pressure applied from the
analysis chamber.
46. The method of daim 37, the pre-chamber further comprising at least one flexible wall and wherein upon
compression of the chamber at the flexible wall the volume of the pre-chamber is reduced.
1 5 47. The method of claim 46, the pre-chamber further comprising a valve at the first end capable of substamially
sealing the pre-chamber from the penetration probe.
48. The method of daim 47, wherein the step of substantially filling the analysis chamber with sample comprises
dosing the vahre and compressing the pre chamber.
49. The method of claim 29, the analysis chamber further comprising at least one flexible wall and wherein upon
20 compression of the analysis chamber at the flexible wall the volume of the analysis chamber is reduced.
50. The method of claim 49, further comprising the steps of:
applying a compressing force to the flexible wall of the analysis diamber to reduce the volume of the
analysis chamber; and
releasing the compressing force, to fonn a partial vacuum in the analysis chamber.
25 51. The method of claim 50, wherein the penetrating step is preceded by the applying step and followed by the
releasing step.
52. The method of claim 30, the fluid sampling device further comprising a compressible bladder In
communication with the analysis chamber, the compressible bladder being capable of applying a positive or a negative
pressure to the analysis chamber.
30 53. The method of daim 52, further comprising the steps of:
applying a compressing force to the compressible bladder, to reduce the volume of the compressible bladder;
and
releasing the compressing force, to forni a partial vacuum in the compressible bladder and analysis chamber.
54. The method of clann 53, wherein the penetrating step is preceded by the applying step and followed by the
35 releasing step.
•14-
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PCTAJSOl/09673
1/6
Top View
RG.I
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PCTAJSOl/09673
RG.2
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PCT/USOl/09673
3/6
Top View
F1G.3
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4/6
Top View
— \
FIG. 4
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RG.5
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PCT/USOl/09673
^10
INTERNATIONAL SEARCH REPORT
Ir ational Application No
PCT/US 01/09673
A. CLASSIFICATION OF SUBJECT MATTER
IPC 7 A61B5/00 A61B10/00
According lo International Palent Ctassificatlon (IPC) or 1o botH nallonal classification and IPC
B. RELDS SEARCHED
Minimum documentation searched (classificalion system followBd by classification symbols)
IPC 7 A61B GOIN
Documentation searched other man minimum documentation to the extent that such documents are inctudad in the lieWs searched
Electronic data t>ase consulted during the international search (name of data base and. where practical, search terms used)
EPO-Internal , WPI Data, PAJ
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category •
Y
A
Y
A
Citation of document, with indication, wtiere appropriate, of Xhe relevant passages
US 4 654 197 A (LILJA JAN E ET AL)
31 March 1987 (1987-03-31)
column 4, line 24 -column 5, line 36;
tables 1-6
US 5 951 492 A (RADWANSKI RYSZARD ET AL)
14 September 1999 (1999-09-14)
column 5, line 26 -column 7, line 28;
tables 1-5
EP 0 796 659 A (SERIM RES CORP)
24 September 1997 (1997-09-24)
column 6, line 12 -column 7, line 46;
tables 1-4
Relevant to claim No.
1,27-29,
32-34,36
2,26,49
1,27-29,
32-34,36
16,17,
21-25,
30,46,54
3-5,7,8,
31.
36-39,50
□
Further documents are listed in the continuation of box C.
Patent family nnembers are listed in annex.
• Speciai categories of died documents :
•A* document defining the general stale of the art which is not
considered lo be of particular relevance
•E* earlier document but published on or after the intemalional
fifing date
•L* document which may throw doubts on priority daim{s) or
which is cited to establish the publication date of another
citation or other special reason (as specified)
'O* document referring lo an oral disdosure. use. exhibition or
other means
•P document published prior to the international filing date but
later than ihe priority date claimed
•T' later document published after the international filing date
or priority date and not in conflict wilh Ihe application but
cited to understand the prindple or theory underlying the
invention
•X' document of particular relevance: the claimed invention
cannot be considered novel or cannot be considered to
involve an inventive step when the document is talten alone
•Y* document of particular relevance: the claimed invention
~ cannol be considered to involve an inventive slep when the
document is combined wilh one or more olher such docu-
ments, such combination being obvious to a person sKilled
in the art.
document member of the same patent family
Date of the actual completion of the international search
8 August 2001
Date of mailing of the intemalional search report
16/08/2001
Name and mailing address of the ISA
European Palent Office, P.B. 58l8 Patentlaan 2
ML - 2280 HV Rijswiji^
Tel. (+31-70) 340-2040. Tx. 31 651 epo nl.
Fax: (+31-70)340-3016
Authorized officer
Weihs, J
Form PCT/lSA/210 (second sheet) (July 1992)
INTERNATIONAL SEARCH REPORT
mromtatlon on patent family member*
Ir ational Application No
PCT/US 01/09673
Patent document
dted in search report
Publication
date
Patent family
membBr(s)
Publication
date
us 4654197
31-03-1987
CA
1252701 A
18-04-
■1989
DE
3475834 D
02-02-
-1989
DK
497384 A,B,
19-04-
-1985
EP
0138152 A
24-04-
-1985
FI
844104 A.B.
19-04-
-1985
JP
1849234 C
07-06-
■1994
JP
5061577 B
06-09-
■1993
JP
60100742 A
04-06-
-1985
NO
844150 A.B,
19-04-
■1985
US 5951492 A 14-09-1999
EP 0796659 A 24-09-1997
us
6099484
A
08-08-2000
AU
3070397
A
05-12-1997
AU
3131097
A
05-12-1997
AU
3206797
A
09-12-1997
AU
3207197
A
05-12-1997
AU
3284797
A
05-12-1997
AU
3368297
A
05-12-1997
DE
19781044
T
03-12-1998
DE
19781046
T
24-12-1998
DE
19781097
T
01-07-1999
DE
19781098
T
24-12-1998
DE
29723357
U
15-10-1998
DE
29723371
U
06-08-1998
DK
64698
A
18-01-1999
DK
64798
A
18-01-1999
DK
67498
A
18-01-1999
EP
0904022
A
31-03-1999
EP
0906062
A
07-04-1999
EP
0955914
A .
17-11-1999
uybbyuy
A
1 7—1 1 —1 QQQ
ES
2121564
A
01-05-2000
ES
2121565
A
01-05-2000
68
2322561
A.B
02-09-1998
GB
2323792
A,B
07-10-1998
GB
2322562
A,B
02-09-1998
GB
2325167
A,B
18-11-1998
. IL
124426
A
01-06-2000
JP
2000511068
T
29-08-2000
WO
9743962
A
27-11-1997
WO
9742882
A
20-11-1997
WO
9742883
A
20-11-1997
WO
9742885
A
20-11-1997
WO
9742886
A
20-11-1997
WO
9742888
A
20-11-1997
US
6015392
A
18-01-2000
US
6056701
A
02-05-2000
US
6183489
B
06-02-2001
US
6048352
A
11-04-2000
us
5879311
A
09-03-1999
US
5857983
A
12-01-1999
CA
2198955 A
22-09-1997
JP
10019741
A
23-01-1998
Foim PCT/ISA/210 (patent family annex) (JuV 1992)
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